E3 ubiquitin ligase FBW7α inhibits cholangiocarcinoma cell proliferation by downregulating c-Myc and cyclin E

Li,Ming; Ouyang,Ling; Zheng,Zhigang; Xiang,Dan; Ti,Aijun; Li,Leihua; Dan,Yuzhen; Yu,Chundong; Li,Wengang

doi:10.3892/or.2017.5432

E3 ubiquitin ligase FBW7α inhibits cholangiocarcinoma cell proliferation by downregulating c-Myc and cyclin E

Authors:
- Ming Li
- Ling Ouyang
- Zhigang Zheng
- Dan Xiang
- Aijun Ti
- Leihua Li
- Yuzhen Dan
- Chundong Yu
- Wengang Li
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Affiliations: Department of Hepatobiliary Pancreas and Vessel Surgery, Chenggong Hospital of Xiamen University, Xiamen, Fujian, P.R. China, Xiamen City Key Laboratory of Biliary Tract Diseases, Chenggong Hospital of Xiamen University, Xiamen, Fujian, P.R. China, Department of General Surgery, The First Hospital of Fuzhou, Fuzhou, Fujian, P.R. China, State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, P.R. China
Published online on: February 7, 2017 https://doi.org/10.3892/or.2017.5432
Pages: 1627-1636

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Abstract

FBW7 (F-box and WD repeat domain-containing 7), also known as CDC4, AGO and SEL10, is the substrate recognition component of an evolutionary conserved SCF (complex of SKP1, CUL1 and F-box protein)-type E3 ubiquitin ligase. It is a recognized tumor suppressor because it targets multiple oncoproteins for ubiquitination-mediated destruction and its mutations are frequently identified in a variety of human malignancies. However, the function of FBW7 in proliferation of cholangiocarcinoma (CCA) remains unknown. We found that overexpression of FBW7α induced CCA cell arrest in G1 phase of cell cycle and inhibited cell proliferation in vitro and CCA xenograft tumor growth, suggesting that FBW7α is a tumor suppressor in CCA progression. Overxpression of FBW7α resulted in the protein degradation of its substrates such as c-Myc and cyclin E which promote CCA cell proliferation. Restoration of the expression of c-Myc, but not cyclin E, rescued the proliferation of FBW7α-overexpression CCA cells. These results suggest that FBW7α plays an essential inhibitory role in CCA progression, indicating that targeting FBW7α substrate c-Myc may be a potential strategy for CCA treatment.

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